Intraocular Retinoblastoma
Conditions
Brief summary
Phase III trial to determine the effectiveness of combining systemic chemotherapy and subtenon carboplatin with ophthalmic therapy in treating children who have intraocular retinoblastoma. Drugs used in chemotherapy, such as vincristine, carboplatin, and etoposide, work in different ways to stop tumor cells from dividing so they stop growing or die. It is not yet known whether systemic chemotherapy and subtenon (under the conjunctiva of the eye) carboplatin combined with ophthalmic therapy is effective in treating intraocular (within the eyeball) retinoblastoma.
Detailed description
PRIMARY OBJECTIVES: I. Determine the event-free survival at 12 months of pediatric patients' eyes with group D intraocular retinoblastoma treated with systemic chemotherapy comprising vincristine, carboplatin, and etoposide, subtenon carboplatin, and local ophthalmic therapy. (Event defined for each eye individually as needed for nonprotocol therapy including nonprotocol chemotherapy, enucleation or any external-beam radiation) SECONDARY OBJECTIVES: I. Determine the event-free survival at 12 months of pediatric patients' eyes with group C retinoblastoma treated with systemic chemotherapy comprising carboplatin, etoposide, vincristine, subtenon carboplatin, and local ophthalmic therapy. II. Determine the acute and long-term toxic effects of these regimens in these patients, including visual outcome and incidence of secondary malignancies. III. Determine the patterns of failure in patients treated with these regimens, in terms of vitreous vs retinal vs both as sites of recurrence. IV. Determine predictors of failure including findings at the on study examination under anesthesia and response status after six courses of chemotherapy. V. Determine the percentage of group C and D eyes separately that can be preserved without enucleation after failing protocol therapy. OUTLINE: This is a multicenter study. Patients receive vincristine IV over 1 minute on day 1 and carboplatin IV over 1 hour and etoposide IV over 1 hour on days 1 and 2. Patients also receive filgrastim (G-CSF) subcutaneously daily beginning on day 3 and continuing until blood counts recover. Patients receive subtenon carboplatin to each group C or D eye on day 0 or 1 prior of courses 2-4 only. Treatment repeats every 28 days for 6 courses in the absence of occurrence of extraocular retinoblastoma or a second malignancy. Beginning with course 3 of systemic chemotherapy, patients undergo local ophthalmic therapy comprising local laser and/or cryotherapy on day 1. Patients are followed with ophthalmology exams every 4-12 weeks until 3 years of age, every 6 months until 5 years of age, and then annually for up to 10 years.
Interventions
Given IV
PROCEDUREcryosurgery
Application of extreme cold to destroy abnormal or diseased tissue.
PROCEDURElaser surgery
Surgery using a laser (instead of a scalpel) to cut tissue
DRUGcarboplatin
Given IV
DRUGetoposide
Given IV
BIOLOGICALfilgrastim
Given subcutaneously
Sponsors
National Cancer Institute (NCI)
Children's Oncology Group
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
No minimum to 17 Years
Healthy volunteers
No
Inclusion criteria
* Diagnosis of bilateral retinoblastoma with at least 1 eye group C or D intraocular retinoblastoma by ophthalmologic examination, defined by the International Classification System for Intraocular Retinoblastoma as the following: * Group C: Discrete localized disease with minimal subretinal and/or vitreous seeding * Subretinal fluid, without prior or concurrent seeding, involving ≤ one quarter of the retina * Local fine vitreous seeding may be present close to discrete tumor * Local subretinal seeding \< 3 mm from tumor * Group D: Diffuse disease with significant vitreous and/or subretinal seeding * Tumor(s) may be massive or diffuse * Subretinal fluid, without prior or concurrent seeding, involving up to total retinal detachment * Diffuse or massive vitreous disease may include greasy seeds or avascular tumor masses * Diffuse subretinal seeding may include subretinal plaques or tumor nodules * Prior enucleation of 1 eye allowed provided the remaining eye is group C or D * No tumor present on histologic examination at the cut end of the optic nerve on any eye enucleated prior to study entry * Evidence of choroidal and/or optic nerve invasion past the lumina cribrosa is allowed * No extraocular retinoblastoma clinically or by MRI of brain and orbits with and without gadolinium or CT scan with and without contrast of brain and orbits * No evidence of systemic metastases by bone marrow, lumbar puncture, bone scan, and/or any other additional test * Performance status - Karnofsky 50-100% (over 16 years of age) * Performance status - Lansky 50-100% (16 and under) * Bilirubin ≤ 1.5 times upper limit of normal (ULN) for age * AST and ALT \< 2.5 times ULN for age * Creatinine adjusted according to age as follows: * No greater than 0.4 mg/dL (≤ 5 months) * No greater than 0.5 mg/dL (6 months -11 months) * No greater than 0.6 mg/dL (1 year-23 months) * No greater than 0.8 mg/dL (2 years-5 years) * No greater than 1.0 mg/dL (6 years-9 years) * No greater than 1.2 mg/dL (10 years-12 years) * No greater than 1.4 mg/dL (13 years and over \[female\]) * No greater than 1.5 mg/dL (13 years to 15 years \[male\]) * No greater than 1.7 mg/dL (16 years and over \[male\]) * Creatinine clearance or radioisotope glomerular filtration rate at least 70 mL/min/1.73m\^2 * Not pregnant or nursing * Fertile patients must use effective contraception * Negative pregnancy test in postmenarchal females * No prior chemotherapy * No other concurrent chemotherapy * No prior radiotherapy * No other concurrent radiotherapy
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Group D Eyes - Treatment Failure Within One Year | One year | Each Group D eye will be classified as experiencing failure within one year after start of treatment: yes or no. The method of Rosner et al. (Biometrics v. 38, 105-114, 1982) will be used to model possible dependence between eyes from the same patient. The point estimate of the probability of treatment failure is reported as the Mean measure type. |
| Group C Eyes - Treatment Failure Within One Year | One year | Each Group C eye will be classified as experiencing failure within one year after start of treatment: yes or no. The method of Rosner et al. (Biometrics v. 38, 105-114, 1982) will be used to model possible dependence between eyes from the same patient. The point estimate of the probability of treatment failure is reported as the Mean measure type. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Event-free Survival (EFS) | One year after study enrollment | Proportion of patients event free at 1 year following enrollment. Event free survival time is computed as the time to study entry until disease relapse/progression, secondary malignancy, or death. |
| Toxicity Associated With Chemotherapy | From date of enrollment until termination of protocol therapy assessed up to 72 weeks | The number of patients that experience CTC Version 4 grade 3 or higher toxicities of any kind. |
| Patterns of Failure for Group C and Group D in Terms of Vitreous vs Patterns of Failure for Group C and Group D in Terms of Vitreous vs Retinal vs Both as Sites of Recurrence | From the date of enrollment assessed up to 36 months | Sites of disease recurrence for Group C and Group D eyes where treatment failure was detected |
| Patterns of Treatment Failure vs. no Treatment Failure for Group C Eyes and Group D Eyes According to Initial Sites of Involvement | From the date of enrollment assessed up to 12 months | The association between the probability of experiencing treatment failure vs. no failure in a C eye and the presence of subretinal seeding (SRS), subretinal fluid (SRF), or vitreal seeding (VS) at the on study ophthalmological examination under anesthesia. The association between the probability of experiencing treatment failure vs. no failure in a D eye and the presence of subretinal seeding (SRS), subretinal fluid (SRF), or vitreal seeding (VS) at the on study ophthalmological examination under anesthesia. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Treatment (Chemotherapy, Surgery) Patients receive liposomal vincristine sulfate IV over 1 minute on day 1 and carboplatin IV over 1 hour and etoposide IV over 1 hour on days 1 and 2. Patients also receive filgrastim (G-CSF) subcutaneously daily beginning on day 3 and continuing until blood counts recover. Patients receive subtenon carboplatin to each group C or D eye on day 0 or 1prior of courses 2-4 only. Treatment repeats every 28 days for 6 courses in the absence of occurrence of extraocular retinoblastoma or a second malignancy. Beginning with course 3 of systemic chemotherapy, patients undergo local ophthalmic therapy comprising local laser surgery and/or cryosurgery on day 1.
liposomal vincristine sulfate: Given IV
cryosurgery: Application of extreme cold to destroy abnormal or diseased tissue.
laser surgery: Surgery using a laser (instead of a scalpel) to cut tissue
carboplatin: Given IV
etoposide: Given IV
filgrastim: Given subcutaneously | 30 |
| Total | 30 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Ineligible | 8 |
| Overall Study | Physician Decision | 1 |
Baseline characteristics
| Characteristic | Treatment (Chemotherapy, Surgery) |
|---|---|
| Age, Continuous | 7.5 months |
| Ethnicity (NIH/OMB) Hispanic or Latino | 11 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 19 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 2 Participants |
| Race (NIH/OMB) Black or African American | 7 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 9 Participants |
| Race (NIH/OMB) White | 12 Participants |
| Region of Enrollment United States | 30 participants |
| Sex: Female, Male Female | 16 Participants |
| Sex: Female, Male Male | 14 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 18 / 22 |
| serious Total, serious adverse events | 0 / 22 |
Outcome results
Primary
Group C Eyes - Treatment Failure Within One Year
Each Group C eye will be classified as experiencing failure within one year after start of treatment: yes or no. The method of Rosner et al. (Biometrics v. 38, 105-114, 1982) will be used to model possible dependence between eyes from the same patient. The point estimate of the probability of treatment failure is reported as the Mean measure type.
Time frame: One year
Population: Four eligible patients had at least one Group C eye to contribute to the analysis
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Treatment (Chemotherapy, Surgery) | Group C Eyes - Treatment Failure Within One Year | 0.25 Probability of treatment failure | Standard Deviation 0.217 |
Primary
Group D Eyes - Treatment Failure Within One Year
Each Group D eye will be classified as experiencing failure within one year after start of treatment: yes or no. The method of Rosner et al. (Biometrics v. 38, 105-114, 1982) will be used to model possible dependence between eyes from the same patient. The point estimate of the probability of treatment failure is reported as the Mean measure type.
Time frame: One year
Population: Twenty eligible patients had at least one Group D eye to contribute to the analysis. A total of 25 Group D eyes were available for analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Treatment (Chemotherapy, Surgery) | Group D Eyes - Treatment Failure Within One Year | 0.52 Probability of treatment failure | Standard Deviation 0.102299 |
Secondary
Event-free Survival (EFS)
Proportion of patients event free at 1 year following enrollment. Event free survival time is computed as the time to study entry until disease relapse/progression, secondary malignancy, or death.
Time frame: One year after study enrollment
Population: 22 eligible patients were considered for this endpoint.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Treatment (Chemotherapy, Surgery) | Event-free Survival (EFS) | 45.45 Percentage probability |
Secondary
Patterns of Failure for Group C and Group D in Terms of Vitreous vs Patterns of Failure for Group C and Group D in Terms of Vitreous vs Retinal vs Both as Sites of Recurrence
Sites of disease recurrence for Group C and Group D eyes where treatment failure was detected
Time frame: From the date of enrollment assessed up to 36 months
Population: 1 patient had at least one Group C eye and 11 patients had at least one Group D eye that experienced treatment failure. There were a total of 13 Group D eyes that experienced treatment failure.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Treatment (Chemotherapy, Surgery) | Patterns of Failure for Group C and Group D in Terms of Vitreous vs Patterns of Failure for Group C and Group D in Terms of Vitreous vs Retinal vs Both as Sites of Recurrence | Vitreal seeding but no retinal seeding | 0 Eyes |
| Treatment (Chemotherapy, Surgery) | Patterns of Failure for Group C and Group D in Terms of Vitreous vs Patterns of Failure for Group C and Group D in Terms of Vitreous vs Retinal vs Both as Sites of Recurrence | Neither retinal seeding nor vitreal seeding | 0 Eyes |
| Treatment (Chemotherapy, Surgery) | Patterns of Failure for Group C and Group D in Terms of Vitreous vs Patterns of Failure for Group C and Group D in Terms of Vitreous vs Retinal vs Both as Sites of Recurrence | Retinal seeding and vitreal seeding | 0 Eyes |
| Treatment (Chemotherapy, Surgery) | Patterns of Failure for Group C and Group D in Terms of Vitreous vs Patterns of Failure for Group C and Group D in Terms of Vitreous vs Retinal vs Both as Sites of Recurrence | Retinal seeding but no vitreal seeding | 1 Eyes |
| Group D Eyes | Patterns of Failure for Group C and Group D in Terms of Vitreous vs Patterns of Failure for Group C and Group D in Terms of Vitreous vs Retinal vs Both as Sites of Recurrence | Retinal seeding but no vitreal seeding | 7 Eyes |
| Group D Eyes | Patterns of Failure for Group C and Group D in Terms of Vitreous vs Patterns of Failure for Group C and Group D in Terms of Vitreous vs Retinal vs Both as Sites of Recurrence | Vitreal seeding but no retinal seeding | 1 Eyes |
| Group D Eyes | Patterns of Failure for Group C and Group D in Terms of Vitreous vs Patterns of Failure for Group C and Group D in Terms of Vitreous vs Retinal vs Both as Sites of Recurrence | Retinal seeding and vitreal seeding | 1 Eyes |
| Group D Eyes | Patterns of Failure for Group C and Group D in Terms of Vitreous vs Patterns of Failure for Group C and Group D in Terms of Vitreous vs Retinal vs Both as Sites of Recurrence | Neither retinal seeding nor vitreal seeding | 4 Eyes |
Secondary
Patterns of Treatment Failure vs. no Treatment Failure for Group C Eyes and Group D Eyes According to Initial Sites of Involvement
The association between the probability of experiencing treatment failure vs. no failure in a C eye and the presence of subretinal seeding (SRS), subretinal fluid (SRF), or vitreal seeding (VS) at the on study ophthalmological examination under anesthesia. The association between the probability of experiencing treatment failure vs. no failure in a D eye and the presence of subretinal seeding (SRS), subretinal fluid (SRF), or vitreal seeding (VS) at the on study ophthalmological examination under anesthesia.
Time frame: From the date of enrollment assessed up to 12 months
Population: According to the initial sites of involvement, 4 patients were analyzed in Group C eyes and 20 patients were analyzed for Group D eyes
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Treatment (Chemotherapy, Surgery) | Patterns of Treatment Failure vs. no Treatment Failure for Group C Eyes and Group D Eyes According to Initial Sites of Involvement | Treatment failure- SRS, SRF, VS | 0 Eyes |
| Treatment (Chemotherapy, Surgery) | Patterns of Treatment Failure vs. no Treatment Failure for Group C Eyes and Group D Eyes According to Initial Sites of Involvement | No treatment failure- SRS and SRF; no VS | 0 Eyes |
| Treatment (Chemotherapy, Surgery) | Patterns of Treatment Failure vs. no Treatment Failure for Group C Eyes and Group D Eyes According to Initial Sites of Involvement | No treatment failure- VS; no SRS; no SRF | 1 Eyes |
| Treatment (Chemotherapy, Surgery) | Patterns of Treatment Failure vs. no Treatment Failure for Group C Eyes and Group D Eyes According to Initial Sites of Involvement | No treatment failure- No SRS; no VS; no SRF | 1 Eyes |
| Treatment (Chemotherapy, Surgery) | Patterns of Treatment Failure vs. no Treatment Failure for Group C Eyes and Group D Eyes According to Initial Sites of Involvement | Treatment failure- SRS; no SRF; no VS | 0 Eyes |
| Treatment (Chemotherapy, Surgery) | Patterns of Treatment Failure vs. no Treatment Failure for Group C Eyes and Group D Eyes According to Initial Sites of Involvement | Treatment failure- SRS and SRF; no VS | 0 Eyes |
| Treatment (Chemotherapy, Surgery) | Patterns of Treatment Failure vs. no Treatment Failure for Group C Eyes and Group D Eyes According to Initial Sites of Involvement | Treatment failure- SRS and VS; no SRF | 0 Eyes |
| Treatment (Chemotherapy, Surgery) | Patterns of Treatment Failure vs. no Treatment Failure for Group C Eyes and Group D Eyes According to Initial Sites of Involvement | Treatment failure- SRF; no SRS; no VS | 1 Eyes |
| Treatment (Chemotherapy, Surgery) | Patterns of Treatment Failure vs. no Treatment Failure for Group C Eyes and Group D Eyes According to Initial Sites of Involvement | Treatment failure- SRF and VS; no SRS | 0 Eyes |
| Treatment (Chemotherapy, Surgery) | Patterns of Treatment Failure vs. no Treatment Failure for Group C Eyes and Group D Eyes According to Initial Sites of Involvement | Treatment failure- VS; no SRS; no SRF | 0 Eyes |
| Treatment (Chemotherapy, Surgery) | Patterns of Treatment Failure vs. no Treatment Failure for Group C Eyes and Group D Eyes According to Initial Sites of Involvement | Treatment failure- No SRS; no VS; no SRF | 0 Eyes |
| Treatment (Chemotherapy, Surgery) | Patterns of Treatment Failure vs. no Treatment Failure for Group C Eyes and Group D Eyes According to Initial Sites of Involvement | No treatment failure- SRS, SRF, VS | 0 Eyes |
| Treatment (Chemotherapy, Surgery) | Patterns of Treatment Failure vs. no Treatment Failure for Group C Eyes and Group D Eyes According to Initial Sites of Involvement | No treatment failure- SRS; no SRF; no VS | 0 Eyes |
| Treatment (Chemotherapy, Surgery) | Patterns of Treatment Failure vs. no Treatment Failure for Group C Eyes and Group D Eyes According to Initial Sites of Involvement | No treatment failure- SRS and VS; no SRF | 0 Eyes |
| Treatment (Chemotherapy, Surgery) | Patterns of Treatment Failure vs. no Treatment Failure for Group C Eyes and Group D Eyes According to Initial Sites of Involvement | No treatment failure- SRF; no SRS; no VS | 1 Eyes |
| Treatment (Chemotherapy, Surgery) | Patterns of Treatment Failure vs. no Treatment Failure for Group C Eyes and Group D Eyes According to Initial Sites of Involvement | No treatment failure- SRF and VS; no SRS | 0 Eyes |
| Group D Eyes | Patterns of Treatment Failure vs. no Treatment Failure for Group C Eyes and Group D Eyes According to Initial Sites of Involvement | No treatment failure- SRS, SRF, VS | 2 Eyes |
| Group D Eyes | Patterns of Treatment Failure vs. no Treatment Failure for Group C Eyes and Group D Eyes According to Initial Sites of Involvement | Treatment failure- SRS; no SRF; no VS | 0 Eyes |
| Group D Eyes | Patterns of Treatment Failure vs. no Treatment Failure for Group C Eyes and Group D Eyes According to Initial Sites of Involvement | Treatment failure- SRF and VS; no SRS | 3 Eyes |
| Group D Eyes | Patterns of Treatment Failure vs. no Treatment Failure for Group C Eyes and Group D Eyes According to Initial Sites of Involvement | Treatment failure- No SRS; no VS; no SRF | 0 Eyes |
| Group D Eyes | Patterns of Treatment Failure vs. no Treatment Failure for Group C Eyes and Group D Eyes According to Initial Sites of Involvement | Treatment failure- SRF; no SRS; no VS | 2 Eyes |
| Group D Eyes | Patterns of Treatment Failure vs. no Treatment Failure for Group C Eyes and Group D Eyes According to Initial Sites of Involvement | No treatment failure- SRS and VS; no SRF | 2 Eyes |
| Group D Eyes | Patterns of Treatment Failure vs. no Treatment Failure for Group C Eyes and Group D Eyes According to Initial Sites of Involvement | No treatment failure- SRF and VS; no SRS | 0 Eyes |
| Group D Eyes | Patterns of Treatment Failure vs. no Treatment Failure for Group C Eyes and Group D Eyes According to Initial Sites of Involvement | No treatment failure- VS; no SRS; no SRF | 2 Eyes |
| Group D Eyes | Patterns of Treatment Failure vs. no Treatment Failure for Group C Eyes and Group D Eyes According to Initial Sites of Involvement | No treatment failure- SRS; no SRF; no VS | 1 Eyes |
| Group D Eyes | Patterns of Treatment Failure vs. no Treatment Failure for Group C Eyes and Group D Eyes According to Initial Sites of Involvement | No treatment failure- No SRS; no VS; no SRF | 1 Eyes |
| Group D Eyes | Patterns of Treatment Failure vs. no Treatment Failure for Group C Eyes and Group D Eyes According to Initial Sites of Involvement | Treatment failure- SRS, SRF, VS | 3 Eyes |
| Group D Eyes | Patterns of Treatment Failure vs. no Treatment Failure for Group C Eyes and Group D Eyes According to Initial Sites of Involvement | Treatment failure- VS; no SRS; no SRF | 2 Eyes |
| Group D Eyes | Patterns of Treatment Failure vs. no Treatment Failure for Group C Eyes and Group D Eyes According to Initial Sites of Involvement | No treatment failure- SRS and SRF; no VS | 2 Eyes |
| Group D Eyes | Patterns of Treatment Failure vs. no Treatment Failure for Group C Eyes and Group D Eyes According to Initial Sites of Involvement | Treatment failure- SRS and SRF; no VS | 3 Eyes |
| Group D Eyes | Patterns of Treatment Failure vs. no Treatment Failure for Group C Eyes and Group D Eyes According to Initial Sites of Involvement | No treatment failure- SRF; no SRS; no VS | 2 Eyes |
| Group D Eyes | Patterns of Treatment Failure vs. no Treatment Failure for Group C Eyes and Group D Eyes According to Initial Sites of Involvement | Treatment failure- SRS and VS; no SRF | 0 Eyes |
Secondary
Toxicity Associated With Chemotherapy
The number of patients that experience CTC Version 4 grade 3 or higher toxicities of any kind.
Time frame: From date of enrollment until termination of protocol therapy assessed up to 72 weeks
Population: 22 eligible patients were evaluable for the occurrence of grade 3 or higher toxicity of any kind.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Treatment (Chemotherapy, Surgery) | Toxicity Associated With Chemotherapy | 10 Patients |